Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UNIPROT:P42574 (caspase-3)
 45,978 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Thimerosal is an organomercury compound with sulfhydryl-reactive properties. The ability of thimerosal to act as a sulfhydryl group is related to the presence of mercury. Due to its antibacterial effect, thimerosal is widely used as preservatives and has been reported to cause chemically mediated side effects. In the present study, we showed that the molecular mechanism of thimerosal induced apoptosis in U937 cells. Thimerosal was shown to be responsible for the inhibition of U937 cells growth by inducing apoptosis. Treatment with 2.5-5 microM thimerosal but not thiosalicylic acid (structural analog of thimerosal devoid of mercury) for 12 h produced apoptosis, G(2)/M phase arrest, and DNA fragmentation in a dose-dependent manner. Treatment with caspase inhibitor significantly reduced thimerosal-induced caspase 3 activation. In addition, thimerosal-induced apoptosis was attenuated by antioxidant Mn (III) meso-tetrakis (4-benzoic acid) porphyrin (Mn-TBAP). These data indicate that the cytotoxic effect of thimerosal on U937 cells is attributable to the induced apoptosis and that thimerosal-induced apoptosis is mediated by reactive oxygen species generation and caspase-3 activation.
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PMID:Thimerosal induces apoptosis and G2/M phase arrest in human leukemia cells. 1664 53

Mercury is a well-known toxic metal, which induces oxidative stress. Pancreatic beta-cells are vulnerable to oxidative stress. The pathophysiological effect of mercury on the function of pancreatic beta-cells remains unclear. The present study was designed to investigate the effects of methylmercury (MeHg)-induced oxidative stress on the cell viability and function of pancreatic beta-cells. The number of viable cells was reduced 24 h after MeHg treatment in a dose-dependent manner with a range from 1 to 20 microM. 2',7'-Dichlorofluorescein fluorescence as an indicator of reactive oxygen species (ROS) formation after exposure of HIT-T15 cells or isolated mouse pancreatic islets to MeHg significantly increased ROS levels. MeHg could also suppress insulin secretion in HIT-T15 cells and isolated mouse pancreatic islets. After 24 h of exposure to MeHg, HIT-T15 cells had a significant increase in mercury levels with a dose-dependent manner. Moreover, MeHg displayed several features of cell apoptosis including an increase of the sub-G1 population and annexin-V binding. Treatment of HIT-T15 cells with MeHg resulted in disruption of the mitochondrial membrane potential and release of cytochrome c from the mitochondria to the cytosol and activation of caspase-3. Antioxidant N-acetylcysteine effectively reversed the MeHg-induced cellular responses. Altogether, our data clearly indicate that MeHg-induced oxidative stress causes pancreatic beta-cell apoptosis and dysfunction.
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PMID:Methylmercury induces pancreatic beta-cell apoptosis and dysfunction. 1691 48

Mercury is a widespread environmental and industrial pollutant that induces serious adverse effects in both humans and the environment. However, the toxicities and its mechanisms have not been fully elucidated. Among the proposed mechanisms of biological toxicities, the intracellular level of thiol group (-SH) and oxidative stress have been widely studied. In this study, production of reactive oxygen species (ROS) by mercuric chloride (2, 4, 6, and 8 ppm as of mercury) was investigated in cultured human bronchial epithelial cells (BEAS-2B cell line). Exposure of cultured cells to mercuric chloride led to cell death, ROS increase, and cytosolic caspase-3 activation. The ROS increase was related to the decreased level of GSH. Chromatin condensation evaluated by 4',6-diamidino-2-phenylindole (DAPI) staining were also shown in mercury-treated cells and this suggest the apoptotic process of cells by mercuric chloride.
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PMID:Induction of reactive oxygen species and apoptosis in BEAS-2B cells by mercuric chloride. 1736 14

Thimerosal is a mercury-containing preservative in some vaccines. The effect of thimerosal on human gastric cancer cells is unknown. This study shows that in cultured human gastric cancer cells (SCM1), thimerosal reduced cell viability in a concentration- and time-dependent manner. Thimerosal caused apoptosis as assessed by propidium iodide-stained cells and caspase-3 activation. Although immunoblotting data revealed that thimerosal could activate the phosphorylation of extracellular signal-regulated kinase, c-Jun NH2-terminal protein kinase, and p38 mitogen-activated protein kinase (p38 MAPK), only SB203580 (a p38 MAPK inhibitor) partially prevented cells from apoptosis. Thimerosal also induced [Ca2+](i) increases via Ca2+ influx from the extracellular space. However, pretreatment with (bis(o-aminophenoxy)ethane-N,N,N',N'-tetraacetate)/AM, a Ca2+ chelator, to prevent thimerosal-induced [Ca2+](i) increases did not protect cells from death. The results suggest that in SCM1 cells, thimerosal caused Ca2+-independent apoptosis via phosphorylating p38 MAPK resulting in caspase-3 activation.
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PMID:Thimerosal-induced apoptosis in human SCM1 gastric cancer cells: activation of p38 MAP kinase and caspase-3 pathways without involvement of [Ca2+]i elevation. 1769 13

The heavy metal mercury (Hg) is known to have immunomodulatory properties affecting lymphocyte signal transduction, death receptor signaling and autoimmunity. In this study we tested the hypothesis that Hg exposure would attenuate T-cell activation and caspase 8 and 3 activity in response to antigenic stimuli. To test this hypothesis, BALB/cJ mice were exposed to 10 mg/l mercuric chloride (HgCl(2)) in their drinking water for 2 weeks followed by injection with 20 microg of the Staphylococcal aureus enterotoxin B (SEB) superantigen. Eighteen hours after SEB challenge, there was a statistically significant reduction in caspase 8 and caspase 3 enzyme activity in the SEB reactive Vbeta8+ T-cells. The attenuated caspase activity in Hg-exposed mice persisted for 48 h after exposure. Moreover, activation of caspase 8 and caspase 3 was reduced by more than 60% in CD95 deficient MRL/MpJ-Fas(lpr) mice demonstrating that caspase 8 and 3 activation in response to SEB is CD95 dependent. In addition to the effects of Hg on caspase activity, expression of the T-cell activation marker CD69 was also attenuated in SEB reactive Vbeta8 T-cells in Hg-exposed mice. Moreover, CD69 expression in MRL/MpJ-Fas(lpr) mice was also reduced. Taken together the caspase and CD69 data support a role for CD95 in promoting a proapoptotic and activated state in SEB responsive T-lymphocytes and this state is attenuated by the autoimmune potentiating environmental agent mercury.
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PMID:Exposure to inorganic mercury in vivo attenuates extrinsic apoptotic signaling in Staphylococcal aureus enterotoxin B stimulated T-cells. 1795 Mar 95

Methylmercury (MeHg) is a known neurotoxin, yet the mechanism for low dose chronic toxicity is still not clear. While N-methyl-D-aspartate receptors (NMDARs) were found to be induced after exposure to MeHg in a mink model, its role on neurotoxicity is not known. The aims of this study were to investigate the expression and the functional roles of NMDARs on the induction of cell death in the human SH-SY 5Y neuroblastoma cell line after exposure to MeHg. NMDARs were measured using a radiolabeled phencyclidine receptor ligand [(3)H] (MK801) and cell death was quantified using fluorogenic substrates specific for caspase-3 (DEVD-AFC) and lactate dehydrogenase (LDH) release. We found a significant increase in NMDARs followed by increased caspase-3 activity after 4 h of exposure to MeHg (0.25-1 microM). Necrotic cell death was found after 4 and 24 h of exposure to MeHg (0.25-5 microM). The NMDAR antagonists dizocilpine ((+)-5-methyl-10,11-dihydro-5H-dibenzo[a,d] cyclohepten-5,10-iminemaleate [(+)-MK801]) and Memantine (1-amino-3,5-dimethyl-adamantane) (10 microM) completely attenuated MeHg-mediated cell death by blocking NMDARs, thus demonstrating the importance of NMDARs in mercury neurotoxicity. Intracellular calcium chelator BAPTA-AM (1 microM) partially attenuated the neurotoxicity effect of 1 microM MeHg. These results suggest that MeHg toxicity can be mediated through the binding and increase of NMDARs.
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PMID:Methylmercury increases N-methyl-D-aspartate receptors on human SH-SY 5Y neuroblastoma cells leading to neurotoxicity. 1859 11

Apoptosis, also known as programmed cell death is a highly regulated and crucial process found in all multicellular organisms. It is not only implicated in regulatory mechanisms of cells, but has been attributed to a number of diseases, i.e. inflammation, malignancy, autoimmunity and neurodegeneration. A variety of toxins can induce apoptosis. Carcinogenic transition metals, viz. cadmium, chromium and nickel promote apoptosis along with DNA base modifications, strand breaks and rearrangements. Generation of reactive oxygen species, accumulation of Ca(2+), upregulation of caspase-3, down regulation of bcl-2, and deficiency of p-53 lead to arsenic-induced apoptosis. In the case of cadmium, metallothionein expression determines the choice between apoptosis and necrosis. Reactive oxygen species (ROS) and p53 contribute in apoptosis caused by chromium. Immuno suppressive mechanisms contribute in lead-induced apoptosis whereas in the case of mercury, p38 mediated caspase activation regulate apoptosis. Nickel kills the cells by apoptotic pathways. Copper induces apoptosis by p53 dependent and independent pathways. Beryllium stimulates the formation of ROS that play a role in Be-induced macrophage apoptosis. Selenium induces apoptosis by producing superoxide that activates p53. Thus, disorders of apoptosis may play a critical role in some of the most debilitating metal-induced afflictions including hepatotoxicity, renal toxicity, neurotoxicity, autoimmunity and carcinogenesis. An understanding of metal-induced apoptosis will be helpful in the development of preventive molecular strategies.
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PMID:Metals and apoptosis: recent developments. 1901 55

The aims of the present study were to apply the AMG technique for localization of mercury at the light and electron microscopic level in the ovary of crucian carp after exposure to mercuric chloride and to find out if this heavy metal induces expression of caspase-3. Depending on the stage of ovarian follicle development, two patterns of mercury accumulation have been found in previtellogenic ovary of crucian carp. The first mercury accumulation pattern has been found in the early previtellogenic oocyte without zona radiata. In these oocytes, mercury accumulates into an ooplasmic region that seems to correspond to the Balbiani body (32-65 microm oocyte diameter), throughout the cytoplasm (84-116 microm oocyte diameter) and in the cortical cytoplasm (approximately 180 microm oocyte diameter). The second mercury accumulation pattern has been found in the late previtellogenic oocyte with cortical alveoli (229-330 microm oocyte diameter). Ultrastructural observations have shown grains of silver-enhanced mercury inside coated vesicles, the cortical lysosome-like bodies or multivesicular bodies and cortical alveoli. Immunohistochemistry reaction for caspase-3 was positive in nuclei of the early previtellogenic oocyte and Balbiani body.
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PMID:Tracing the accumulation and effects of mercury uptake in the previtellogenic ovary of crucian carp, Carassius auratus gibelio by autometallography and caspase-3 immunohistochemistry. 1908 30

Mercury is a well-known highly toxic metal. In this study, we characterize and investigate the cytotoxicity and its possible mechanisms of inorganic mercury in pancreatic beta-cells. Mercury chloride (HgCl2) dose-dependently decreased the function of insulin secretion and cell viability in pancreatic beta-cell-derived HIT-T15 cells and isolated mouse pancreatic islets. HgCl2 significantly increased ROS formation in HIT-T15 cells. Antioxidant N-acetylcysteine effectively reversed HgCl2-induced insulin secretion dysfunction in HIT-T15 cells and isolated mouse pancreatic islets. Moreover, HgCl2 increased sub-G1 hypodiploids and annexin-V binding in HIT-T15 cells, indicating that HgCl2 possessed ability in apoptosis induction. HgCl2 also displayed several features of mitochondria-dependent apoptotic signals including disruption of the mitochondrial membrane potential, increase of mitochondrial cytochrome c release and activations of poly (ADP-ribose) polymerase (PARP) and caspase 3. Exposure of HIT-T15 cells to HgCl2 could significantly increase both apoptotic and necrotic cell populations by acridine orange/ethidium bromide dual staining. Meanwhile, HgCl2 could also trigger the depletion of intracellular ATP levels and increase the LDH release from HIT-T15 cells. These HgCl2-induced cell death-related signals could be significantly reversed by N-acetylcysteine. The intracellular mercury levels were markedly elevated in HgCl2-treated HIT-T15 cells. Taken together, these results suggest that HgCl2-induced oxidative stress causes pancreatic beta-cell dysfunction and cytotoxicity involved the co-existence of apoptotic and necrotic cell death.
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PMID:Inorganic mercury causes pancreatic beta-cell death via the oxidative stress-induced apoptotic and necrotic pathways. 2000 36

Mercury, one of the widespread pollutants in the world, induces oxidative stress and dysfunction in many cell types. Alveolar type II epithelial cells are known to be vulnerable to oxidative stress. Alveolar type II epithelial cells produce and secrete surfactants to maintain morphological organization, biophysical functions, biochemical composition, and immunity in lung tissues. However, the precise action and mechanism of mercury on alveolar type II epithelial cell damage remains unclear. In this study, we investigate the effect and possible mechanism of methylmercury chloride (MeHgCl) on the human lung invasive carcinoma cell line (Cl1-0) and mouse lung tissue. Cl1-0 cells were exposed to MeHgCl (2.5-10 microM) for 24-72 h. The results showed a decrease in cell viability and an increase in malondialdehyde (MDA) level and ROS production at 72 h after MeHgCl exposure in a dose-dependent manner. Caspase-3 activity, sub-G1 contents and annexin-V binding were dramatically enhanced in Cl1-0 cells treated with MeHgCl. MeHgCl could also activate Bax, release cytochrome c, and cleave poly(ADP-Ribose) polymerase (PARP), and decrease surfactant proteins mRNA levels. Moreover, in vivo study showed that mercury contents of blood and lung tissues were significantly increased after MeHgCl treatment in mice. The MDA levels in plasma and lung tissues were also dramatically raised after MeHgCl treatment. Lung tissue sections of MeHgCl-treated mice showed pathological fibrosis as compared with vehicle control. The mRNA levels of proteins in apoptotic signaling, including p53, mdm-2, Bax, Bad, and caspase-3 were increased in mice after exposure to MeHgCl. In addition, the mRNA levels of surfactant proteins (SPs), namely, SP-A, SP-B, SP-C, and SP-D (alveolar epithelial cell functional markers) were significantly decreased. These results suggest that MeHgCl activates an oxidative stress-induced mitochondrial cell death in alveolar epithelial cells.
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PMID:Methylmercury chloride induces alveolar type II epithelial cell damage through an oxidative stress-related mitochondrial cell death pathway. 2015 10


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